Tricyclic 3-keto derivatives of 6-O-methylerthromycin

ABSTRACT

The present invention relates to compounds of the formula 1                    
     and to pharmaceutically acceptable salts thereof, wherein R 1 -R 7  are as defined herein. The compounds of formula 1 are useful as antibiotic agents. The invention further relates to pharmaceutical compositions and methods of treating bacterial infection using such compounds, and to methods of making the compounds of formula 1.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/IB99/00855, filed May 12, 1999, which claims the benefit of U.S.provisional application no. 60/087,798, filed Jun. 3, 1998.

BACKGROUND OF THE INVENTION

This invention relates to tricyclic 3-keto derivatives of6-O-methylerythromycin A. The compounds of this invention are useful asantibiotic agents in mammals, including man, as well as in fish andbirds. The compounds of the present invention are broad-spectrummacrolide antibiotics that are effective against infections caused bycertain gram-positive and gram-negative bacteria as well as protozoa.

Macrolide antibiotics are known to be useful in the treatment of a broadspectrum of bacterial infections and protozoa infections in mammals,fish and birds. Such antibiotics include various derivatives oferythromycin A such as azithromycin which is commercially available andis referred to in U.S. Pat. Nos. 4,474,768 and 4,517,359, both of whichare incorporated herein by reference in their entirety. Additionalmacrolides are referred to in U.S. patent application Ser. No.60/063676, filed Oct. 29, 1997 (Yong-Jin Wu), U.S. application Ser. No.60/063161, filed Oct. 29, 1997 (Yong-Jin Wu), U.S. application Ser. No.60/054866, filed Aug. 6, 1997(Hiroko Masamune, Yong-Jin Wu, TakushiKaneko and Paul R. McGuirk), all of which are incorporated herein byreference in their entirety. Like azithromycin and other macrolideantibiotics, the novel macrolide compounds of the present inventionpossess activity against various bacterial infections and protozoainfections as described below.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula

and to pharmaceutically acceptable salts thereof, wherein:

R¹ is selected from H, —(CR⁴R⁵)_(m)R⁶, —C(O)(CR⁴R⁵)_(m)R⁶,—C(O)O(CR⁴R⁵)_(m)R⁶, —C(O)NR⁴(CR⁴R⁵)_(m)R^(6,) wherein m is an integerranging from 0 to 6 and both R⁴ and R⁵ may vary for each iteration wherem is greater than 1;

each R² and R³ are independently selected from H and C₁-C₁₈ alkyl,wherein one or two carbons of said alkyl are optionally replaced by aheteroatom selected from O, S and N, and are optionally substituted by 1to 3 substituents independently selected from the group consisting of—C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl, C₁-C₁₀ alkanoyl, halo, nitro,cyano, C₁-C₁₀ alkyl, 4-10 membered heterocyclic, C₆-C₁₀ aryl,—NH(C₁-C₁₀)alkyl, —S(C₁-C₁₀ alkyl), —SO(C₁-C₁₀)alkyl, —SO₂(C₁-C₁₀)alkyland —SO₂N(C₁-C₁₀)alkyl, provided that two O atoms, two S atoms or an Sand an O atom are not bonded to each other;

each R⁴ and R⁵ are independently selected from H, halo and C₁-C₆ alkyl,wherein 1 to 3 carbons of said alkyl are optionally replaced by aheteroatom selected from O, S and N and each R⁴ and R⁵ may varyindependently when m is greater than 1, provided that two O atoms, two Satoms or an S and an O atom are not bonded to each other; or

each R⁴ and R⁵ taken together with the carbon to which they are attachedcan form a 3-10 membered ring, wherein one or more carbons of said ringare optionally replaced by a heteroatom selected from O, S and N, andare optionally substituted by 1 to 3 substituents independently selectedfrom the group consisting of —C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl,C₁-C₁₀ alkanoyl, halo, nitro, cyano, C₁-C₁₀ alkyl, 4-10 memberedheterocyclic, C₆-C₁₀ aryl, —NH(C₁-C₁₀)alkyl, —N((C₁-C₁₀)alkyl)₂,—S(C₁-C₁₀)alkyl, —SO(C₁-C₁₀)alkyl, —SO₂(C₂(C₁-C₁₀)alkyl and—SO₂N(C₁-C₁₀)alkyl, provided that two O atoms, two S atoms or an S andan O atom are not bonded to each other;

R⁶ is (C₁-C₁₈)alkyl, a 4-10 membered heterocyclic or C₆-C₁₀ aryl,wherein 1 to 3 carbons of said alkyl are optionally replaced by aheteroatom selected from O, S and N and said heterocycic and aryl groupsare optionally substituted by 1 to 3 substituents independently selectedfrom the group consisting of —C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl,C₁-C₁₀ alkanoyl, halo, nitro, cyano, (C₁-C₁₀) alkyl, —NH(C₁-C₁₀)alkyl,—N((C₁-C₁₀)alkyl)₂, —S(C₁-C₁₀ alkyl), —SO(C₁-C₁₀)alkyl,—SO₂(C₁-C₁₀)alkyl and —SO₂N(C₁-C₁₀)alkyl, provided that two O atoms, twoS atoms or an S and an O atom are not bonded to each other; and

R⁷ is H, —C(O)O(C₁-C₁₈)alkyl or —C(O)(C₁-C₁₈)alkyl, wherein 1 to 3carbons of said alkyl are optionally replaced by a heteroatom selectedfrom O, S and N and wherein in the alkyl portion of said alkanoyl one ortwo carbons optionally may be replaced by a heteroatom selected from O,S and N, provided that two O atoms, two S atoms or an S and an O atomare not bonded to each other.

More specific embodiments of this invention include compounds of formula1 wherein R⁷ is H.

More specific embodiments of this invention include compounds of formula1 wherein R³ is H.

More specific embodiments of this invention include compounds of formula1 wherein R³=R²=H.

More specific embodiments of this invention include compounds of formula1 wherein R³=R²=R⁷=H.

Other more specific embodiments of this invention include compounds offormula 1 wherein R² is (CH₂)_(m) R⁶, wherein m is an integer rangingfrom 0 to 6. Specific embodiments of compounds of formula 1 wherein R²is (CH₂)_(m) R⁶ and wherein m is an integer ranging from 0 to 6 includesuch compounds wherein R⁶ is quinolin-4-yl, quinolin-5-yl,quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, 4-pyridin-3-yl-imidazol-1-yl,or imidazo(4,5-b)pyridin-3-yl. More specific embodiments of thisinvention include compounds of formula 1 wherein R² is (CH₂)_(m) R⁶ andm is 3. Specific embodiments of compounds of formula 1 wherein R² is(CH₂)_(m) R⁶ and m is 3 include such compounds wherein R⁶ isquinolin-4-yl, quinolin-5-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl,4-pyridin-3-yl-imidazol-1-yl or imidazo(4,5-b)pyridin-3-yl.

Examples of preferred compounds of this invention include:

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-quinolin-4-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=7-methoxy-quinolin-4-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-benzoimidazol-1-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H, R¹=3-indol-1-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-indazol-1-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-carbazol-1-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H, R¹=3-(5-phenyl-1H-pyrrol-2-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(4-phenyl-imidazol-1-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(imidazo(4,5-b)pyridin-3-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(4-pyridin-3-yl-imidazol-1-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(3-(4-chlorophenyl)-(1,2,4)oxadizol-5-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(3-(4-methoxyphenyl)-(1,2,4)oxadizol-5-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(3-(4-pyridin-4-yl)-(1,2,4)oxadizol-5-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-benzotriazol-1-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-benzotriazol-2-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(1H-indol-3-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-pyridin-4-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-pyridin-3-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-pyridin-2-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H, R¹=3-phenylpropyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(2-methoxyphenyl)-propyl ;

the compound of formula 1 wherein R⁷=H, R³=R²=H, R¹=3-furan-2-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-thiophen-2-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-pyrrol-1-yl-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(2-pyridin-3-yl-thiazol-4-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(2-phenyl-thiazol-5-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(2-phenyl-thiazol-5-yl)-propyl;

the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(4-phenyl1H-imidazol-2-yl)-propyl;

and pharmaceutically acceptable salts of the foregoing compounds.

The invention also relates to a pharmaceutical composition for thetreatment of a bacterial infection or protozoal infection in a mammal,fish, or bird which comprises a therapeutically effective amount of acompound of formula 1, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating a bacterial infectionor a protozoal infection in a mammal, fish, or bird which comprisesadministering to said mammal, fish or bird a therapeutically effectiveamount of a compound of formula 1 or a pharmaceutically acceptable saltthereof.

The term “treatment”, as used herein, unless otherwise indicated,includes the treatment or prevention of a bacterial infection orprotozoal infection as provided in the method of the present invention.

As used herein, unless otherwise indicated, the term “bacterialinfection(s)” or “protozoa infection” includes bacterial infections andprotozoa infections that occur in mammals, fish and birds as well asdisorders related to bacterial infections and protozoa infections thatmay be treated or prevented by administering antibiotics such as thecompounds of the present invention. Such bacterial infections andprotozoa infections and disorders related to such infections include thefollowing: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis,and mastoiditis related to infection by Streptococcus pneumoniae,Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, orPeptostreptococcus spp.; pharynigitis, rheumatic fever, andglomerulonephritis related to infection by Streptococcus pyogenes,Groups C and G streptococci, Clostridium diptheriae, or Actinobacillushaemolyticum; respiratory tract infections related to infection byMycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae,Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin andsoft tissue infections, abscesses and osteomyelitis, and puerperal feverrelated to infection by Staphylococcus aureus, coagulase-positivestaphylococci (i.e., S. epidermidis, S. hemolyticus, etc.),Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groupsC-F (minute-colony streptococci), viridans streptococci, Corynebacteriumminutissimum, Clostridium spp., or Bartonella henselae; uncomplicatedacute urinary tract infections related to infection by Staphylococcussaprophyticus or Enterococcus spp.; urethritis and cervicitis; andsexually transmitted diseases related to infection by Chlamydiatrachomatis, Haemophilus ducreyl, Treponema pallidum, Ureaplasmaurealyticum, or Neiserria gonorrheae; toxin diseases related toinfection by S. aureus (food poisoning and Toxic shock syndrome), orGroups A, B, and C streptococci; ulcers related to infection byHelicobacter pylori; systemic febrile syndromes related to infection byBorrelia recurrentis; Lyme disease related to infection by Borreliaburgdorferi; conjunctivitis, keratitis, and dacrocystitis related toinfection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S.pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminatedMycobacterium avium complex (MAC) disease related to infection byMycobacterium avium, or Mycobacterium intracellulare; gastroenteritisrelated to infection by Campylobacter jejuni; intestinal protozoarelated to infection by Cryptosporidium spp.; odontogenic infectionrelated to infection by viridans streptococci; persistent cough relatedto infection by Bordetella pertussis; gas gangrene related to infectionby Clostridium perfringens or Bacteroides spp.; and atherosclerosisrelated to infection by Helicobacter pylori or Chlamydia pneumoniae.Bacterial infections and protozoa infections and disorders related tosuch infections that may be treated or prevented in animals include thefollowing: bovine respiratory disease related to infection by P. haem.,P multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric diseaserelated to infection by E. Coli or protozoa (i.e., coccidia,cryptosporidia, etc.); dairy cow mastitis related to infection by Staph.aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae,Klebsiella spp., Corynebacterium, or Enterococcus spp.; swinerespiratory disease related to infection by A. pleuro., P. multocida, orMycoplasma spp.; swine enteric disease related to infection by E. coli,Lawsonia intracellularis, Salmonella, or Serpulina hyodyisinteriae; cowfootrot related to infection by Fusobacterium spp.; cow metritis relatedto infection by E coli; cow hairy warts related to infection byFusobacterium necrophorum or Bacteroides nodosus; cow pink-eye relatedto infection by Moraxella bovis; cow premature abortion related toinfection by protozoa (i.e. neosporium); urinary tract infection in dogsand cats related to infection by E coli; skin and soft tissue infectionsin dogs and cats related to infection by Staph. epidermidis, Staph.intermedius, coagulase neg. Staph. or P. multocida; and dental or mouthinfections in dogs and cats related to infection by Alcaligenes spp.,Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium,Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterialinfections and protozoa infections and disorders related to suchinfections that may be treated or prevented in accord with the method ofthe present invention are referred to in J. P. Sanford et al., “TheSanford Guide To Antimicrobial Therapy,” 26th Edition, (AntimicrobialTherapy, Inc., 1996).

The invention also relates to a method of preparing a compound of theformula

and to pharmaceutically acceptable salts thereof, wherein:

R¹ is selected from H, —(CR⁴R⁵)_(m)R⁶, —C(O)(CR⁴R⁵)_(m)R⁶,—C(O)O(CR⁴R⁵)_(m)R⁶, —C(O)NR⁴(CR⁴R⁵)_(m)R⁶, wherein m is an integerranging from 0 to 6 and both R⁴ and R⁵ may vary for each iteration wherem is greater than 1;

each R² and R³ are independently selected from H and C₁-C₁₈ alkyl,wherein one or two carbons of said alkyl are optionally replaced by aheteroatom selected from O, S and N, and are optionally substituted by 1to 3 substituents independently selected from the group consisting of—C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl, C₁-C₁₀ alkanoyl, halo, nitro,cyano, C₁-C₁₀ alkyl, 4-10 membered heterocyclic, C₆-C₁₀ aryl,—NH(C₁-C₁₀)alkyl, —S(C₁-C₁₀ alkyl), —SO(C₁-C₁₀)alkyl, —SO₂(C₁-C₁₀)alkyland —SO₂N(C₁ 14 C₁₀)alkyl, provided that two O atoms, two S atoms or anS and an O atom are not bonded to each other;

each R⁴ and R⁵ are independently selected from H, halo and C₁-C₆ alkyl,wherein 1 to 3 carbons of said alkyl are optionally replaced by aheteroatom selected from O, S and N and each R⁴ and R⁵ may varyindependently when m is greater than 1, provided that two O atoms, two Satoms or an S and an O atom are not bonded to each other; or

each R⁴ and R⁵ taken together with the carbon to which they are attachedcan form a 3-10 membered ring, wherein one or more carbons of said ringare optionally replaced by a heteroatom selected from O, S and N, andare optionally substituted by 1 to 3 substituents independently-selectedfrom the group consisting of —C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl,C₁-C₁₀ alkanoyl, halo, nitro, cyano, C₁-C₁₀ alkyl, 4-10 memberedheterocyclic, C₆-C₁₀ , aryl, —NH(C₁-C₁₀)alkyl, —N((C₁-C₁₀)alkyl)₂,—S(C₁-C₁₀)alkyl, —SO(C₁-C₁₀)alkyl, —SO₂(C₂(C₁-C₁₀)alkyl and—SO₂N(C₁-C₁₀)alkyl, provided that two O atoms, two S atoms or an S andan O atom are not bonded to each other;

R⁶ is (C₁-C₁₈)alkyl, a 4-10 membered heterocyclic or C₆-C₁₀ aryl,wherein 1 to 3 carbons of said alkyl are optionally replaced by aheteroatom selected from O, S and N and said heterocycic and aryl groupsare optionally substituted by 1 to 3 substituents independently selectedfrom the group consisting of —C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl,C₁-C₁₀ alkanoyl, halo, nitro, cyano, (C₁-C₁₀) alkyl, —NH(C₁-C₁₀)alkyl,—N((C₁-C₁₀)alkyl)₂, —S(C₁-C₁₀ alkyl), —SO(C₁-C₁₀ )alkyl,—SO₂(C₁-C₁₀)alkyl and —SO₂N(C₁-C₁₀)alkyl, provided that two O atoms, twoS atoms or an S and an O atom are not bonded to each other; and

R⁷ is H, —C(O)O(C₁-c₁₈)alkyl or —C(O)(C₁-c₁₈)alkyl, wherein 1to 3carbons of said alkyl are optionally replaced by a heteroatom selectedfrom O, S and N and wherein in the alkyl portion of said alkanoyl one ortwo carbons optionally may be replaced by a heteroatom selected from O,S and N, provided that two O atoms, two S atoms or an S and an O atomare not bonded to each other, which comprises treating a compound of theformula

wherein R⁷ and R¹ are as defined above, with a compound of the formulaR³R²C=O, wherein R³ and R² are as defined for the compound of formula 1,in the presence of an acid. An example of a preferred compound of theformula R³R²C=O is CH₂O. Examples of suitable acids include, forexample, acetic acid, formic acid, para-toluene sulfonic acid andproprionic acid. The acid may be in the presence of a suitable solvent,such as for example, CH₂Cl₂, C₆H₆, CHCl₃, acetonitrile,dimethylformamide, tetrahydrofuran, dioxane and dichloroethane.

The compound of formula 2 can be prepared as described in U.S. patentapplication Ser. No. 60/049349, filed Jun. 11, 1997 (Yong-Jin Wu), andin corresponding International Application no. WO 9856800, publishedDec. 17, 1998, which is herein incorporated by reference in itsentirety.

The present invention further relates to a compound of the formula

and to pharmaceutically acceptable salts thereof, wherein:

R¹ is selected from H, —(CR⁴R⁵)_(m)R⁶, —C(O)(CR⁴R⁵)_(m)R⁶,—C(O)O(CR⁴R⁵)_(m)R⁶, —C(O)NR⁴(CR⁴R⁵)_(m)R⁶, wherein m is an integerranging from 0 to 6 and both R⁴ and R⁵ may vary for each iteration wherem is greater than 1;

each R⁴ and R⁵ are independently selected from H, halo and C₁-C₆ alkyl,wherein 1 to 3 carbons of said alkyl are optionally replaced by aheteroatom selected from O, S and N and each R⁴ and R⁵ may varyindependently when m is greater than 1, provided that two O atoms, two Satoms or an S and an O atom are not bonded to each other; or

each R⁴ and R⁵ taken together with the carbon to which they are attachedcan form a 3-10 membered ring, wherein one or more carbons of said ringare optionally replaced by a heteroatom selected from O, S and N, andare optionally substituted by 1 to 3 substituents independently selectedfrom the group consisting of —C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl,C₁-C₁₀ alkanoyl, halo, nitro, cyano, C₁-C₁₀ alkyl, 4-10 memberedheterocyclic, C₆-C₁₀ aryl, —NH(C₁-C₁₀)alkyl, —N((C₁-C₁₀)alkyl)₂,—S(C₁-C₁₀)alkyl, —SO(C₁-C₁₀)alkyl, —SO₂(C₂(C₁-C₁₀)alkyl and—SO₂N(C₁-C₁₀)alkyl, provided that two O atoms, two S atoms or an S andan O atom are not bonded to each other; and

R⁶ is (C₁-C₁₈)alkyl, a 4-10 membered heterocyclic or C₆-C₁₀ aryl,wherein 1 to 3 carbons of said alkyl are optionally replaced by aheteroatom selected from O, S and N and said heterocycic and aryl groupsare optionally substituted by 1 to 3 substituents independently selectedfrom the group consisting of —C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl,C₁-C₁₀ alkanoyl, halo, nitro, cyano, (C₁-C₁₀) alkyl, —NH(C₁-C₁₀)alkyl,—N((C₁-C₁₀)alkyl)₂, —S(C₁-C₁₀ alkyl), —SO(C₁-C₁₀)alkyl,—SO₂(C₁-C₁₀)alkyl and —SO₂N(C₁-C₁₀)alkyl, provided that two O atoms, twoS atoms or an S and an O atom are not bonded to each other.

The present invention further relates to a compound of the formula

and pharmaceutically acceptable salts thereof, wherein:

R¹ is selected from the group consisting of: phenylbutyl,3-quinolin-4-yl-propyl, 3-(4-phenyl-imadazol-1-yl)-propyl,3-(2-methoxyphenyl)-propyl, 3-furan-2-yl-propyl,3-benzoimidazol-1-yl-propyl, 3-indazol-1-yl-propyl,3-(4-hydroxy-phenyl)-propyl, 3-(1H-indol-3-yl)-propyl, and3-(4-pyridin-3-yl-imidazol-1-yl)-propyl.

In the chemical structures depicted herein, a wavy line indicates thatthe stereochemistry at the chiral center to which the wavy line isconnected is either an R or S configuration where the wavy line isconnected to a carbon atom. In the compound of formula 2, the wavy lineconnected to the oxime nitrogen at position 9 of the macrolide ringindicates that the hydroxy moiety is in an E or Z configuration.

The term “halo”, as used herein, unless otherwise indicated, meansfluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloroand bromo.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, cyclic orbranched moieties. Said alkyl group may include one or two double ortriple bonds. It is understood that for cyclic moieties at least threecarbon atoms are required in said alkyl group.

The term “alkanoyl”, as used herein, unless otherwise indicated,includes -C(O)-alkyl groups wherein “alkyl” is as defined above.

The term “aryl”, as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl.

The term “4-10 membered heterocyclic”, as used herein, unless otherwiseindicated, includes aromatic and non-aromatic heterocyclic groupscontaining one or more heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4-10 atoms in its ring system.Non-aromatic heterocyclic groups include groups having only 4 atoms intheir ring system, but aromatic heterocyclic groups must have at least 5atoms in their ring system. The heterocyclic groups include benzo-fusedring systems and ring systems substituted with one or more oxo moieties.An example of a 5 membered heterocyclic group is thiazolyl, and anexample of a 10 membered heterocyclic group is quinolinyl. Examples ofnon-aromatic heterocyclic groups are pyrrolidinyl, piperidino,morpholino, thiomorpholino and piperazinyl. Examples of aromaticheterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl andthiazolyl. In general, acceptable 4-10 membered heterocyclic groupsinclude those derived from one of the following: furan, thiophene,2H-pyrrole, pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine,1,3-dioxolane, oxazole, thiazole, imidazole, 2-imidazole, imidazolidine,pyrazole, 2-pyrazoline, pyrazolidine, isoxazole, isothiazole,1,2,3-oxadiazole, 1,2,3-triazole, 1,3,4-thiadiazole, 2H-pyran, 4H-pyran,pyridine, piperidine, 1,4-dioxane, 1,3-dioxane, morpholine,1,4-dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine,piperazine, 1,3,5-triazine, 1,3,5-trithiane, indolizine, indole,isoindole, 3H-indole, indoline, benzofuran, benzothiophene, 1H-indazole, benzimidazole, benzthiazole, purine, 4H-quinolizine,quinoline, isoquinoline, cinnoline, phthalazine, quinazoline,quinoxaline, 1,8-naphthyridine, pteridine, quinuclidine, carbazole,acridine, phenazine, phenothiazine, phenoxazine, tetrazole, thietane andazetidine.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of formula 1. The compounds of formula 1that are basic in nature are capable of forming a wide variety of saltswith various inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds of formula 1 are those that form non-toxic acid additionsalts, i.e., salts containing pharmacologically acceptable anions, suchas the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate,salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate,ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds of the formula 1 that are acidic in nature, are capableof forming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline earth metalsalts and particularly, the sodium and potassium salts.

The present invention also includes all radiolabelled forms of thecompounds of formula 1, and pharmaceutically acceptable salts thereof,wherein the radiolabel is selected from ³H, ¹¹C and ¹⁴C. Suchradiolabelled compounds are useful as research or diagnostic tools.

Certain compounds of formula 1 may have asymmetric centers and thereforeexist in different enantiomeric forms. This invention relates to the useof all optical isomers and stereoisomers of the compounds of formula 1and mixtures thereof. The compounds of formula 1 may also exist astautomers. This invention relates to the use of all such tautomers andmixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION

The preparation of the compounds of the present invention is illustratedin the following Scheme.

The Scheme illustrates the general synthesis of the compounds of thepresent invention. In the Scheme, the starting compound of formula 2 canbe prepared as described in U.S. patent application Ser. No. 60/049349,filed Jun. 11, 1997 (Yong-Jin Wu), and in corresponding InternationalApplication no. WO 9856800, published Dec. 17, 1998, which are hereinincorporated by reference in its entirety.

The tricyclic nitrone of the compound of formula 1 can be prepared bytreating the starting compound of formula 2 with a compound of theformula R³R²C=O, wherein R³ and R² are defined as specified in thecompound of formula 1, in the presence of an acid such as formic acid,acetic acid, para-toluenesulfonic acid or proprionic acid in a solventsuch as CHCl₃, chloroform, benzene, acetonitrile, dimethylformamide(DMF), tetrahydrofuran (THF), dioxane or dichloroethane, at atemperature within the range from about 10 to about 90° C. for a periodof about 1 to 18 hours.

The compounds of the present invention may have asymmetric carbon atoms.Such diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixtures into a diastereomricmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomer mixtures and pureenantiomers are considered as part of the invention.

The compounds of formula 1 that are basic in nature are capable offorming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate the compound of formula 1 from the reaction mixture asa pharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the basecompounds of this invention are readily prepared by treating the basecompound with a substantially equivalent amount of the chosen mineral ororganic acid in an aqueous solvent medium or in a suitable organicsolvent, such as methanol or ethanol. Upon careful evaporation of thesolvent, the desired solid salt is readily obtained. The desired acidsalt can also be precipitated from a solution of the free base in anorganic solvent by adding to the solution an appropriate mineral ororganic acid.

Those compounds of the formula 1 that are acidic in nature, are capableof forming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline-earth metalsalts and particularly, the sodium and potassium salts. These salts maybe prepared by conventional techniques. The chemical bases which areused as reagents to prepare the pharmaceutically acceptable base saltsof this invention are those which form non-toxic base salts with theacidic compounds of formula 1. Such non-toxic base salts include thosederived from such pharmacologically acceptable cations as sodium,potassium calcium and magnesium, etc. These salts can be prepared bytreating the corresponding acidic compounds with an aqueous solutioncontaining the desired pharmacologically acceptable cations, and thenevaporating the resulting solution to dryness, preferably under reducedpressure. Alternatively, they may also be prepared by mixing loweralkanolic solutions of the acidic compounds and the desired alkali metalalkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction and maximum yields of the desired final product

The activity of the compounds of the present invention against bacterialand protozoa pathogens is demonstrated by the compound's ability toinhibit growth of defined strains of human (Assay I) or animal (AssaysII and II) pathogens.

ASSAY I

Assay I, described below, employs conventional methodology andinterpretation criteria and is designed to provide direction forchemical modifications that may lead to compounds that circumventdefined mechanisms of macrolide resistance. In Assay I, a panel ofbacterial strains is assembled to include a variety of target pathogenicspecies, including representatives of macrolide resistance mechanismsthat have been characterized. Use of this panel enables the chemicalstructure/activity relationship to be determined with respect topotency, spectrum of activity, and structural elements or modificationsthat may be necessary to obviate resistance mechanisms. Bacterialpathogens that comprise the screening panel are shown in the tablebelow. In many cases, both the macrolide-susceptible parent strain andthe macrolide-resistant strain derived from it are available to providea more accurate assessment of the compound's ability to circumvent theresistance mechanism. Strains that contain the gene with the designationof ermA/ermB/ermC are resistant to macrolides, lincosamides, andstreptogramin B antibiotics due to modifications (methylation) of 23SrRNA molecules by an Erm methylase, thereby generally prevent thebinding of all three structural classes. Two types of macrolide effluxhave been described; msrA encodes a component of an efflux system instaphylococci that prevents the entry of macrolides and streptograminswhile mefA/E encodes a transmembrane protein that appears to efflux onlymacrolides. Inactivation of macrolide antibiotics can occur and can bemediated by either a phosphorylation of the 2′-hydroxyl (mph) or bycleavage of the macrocyclic lactone (esterase). The strains may becharacterized using conventional polymerase chain reaction (PCR)technology and/or by sequencing the resistance determinant. The use ofPCR technology in this application is described in J. Sutcliffe et al.,“Detection Of Erythromycin-Resistant Determinants By PCR”, AntimicrobialAgents and Chemotherapy, 40(11), 2562-2566 (1996). The antibacterialassay is performed in microtiter trays and interpreted according toPerformance Standards for Antimicrobial Disk Susceptibility Tests—SixthEdition; Approved Standard, published by The National Committee forClinical Laboratory Standards (NCCLS) guidelines; the minimum inhibitoryconcentration (MIC) is used to compare strains. acr AB or acr AB-likeindicates that an intrinsia multidrug efflux pump exists in the strain.Compounds are initially dissolved in dimethylsulfoxide (DMSO) as 40mg/ml stock solutions.

Strain Designation Macrolide Resistance Mechanism(s) Staphylococcusaureus 1116 susceptible parent Staphylococcus aureus 1117 ermBStaphylococcus aureus 0052 susceptible parent Staphylococcus aureus 1120ermC Staphylococcus aureus 1032 msrA, mph, esterase Staphylococcushemolyticus 1006 msrA, mph Streptococcus pyogenes 0203 susceptibleparent Streptococcus pyogenes 1079 ermB Streptococcus pyogenes 1062susceptible parent Streptococcus pyogenes 1061 ermB Streptococcuspyogenes 1064 mefA Streptococcus agalactiae 1024 susceptible parentStreptococcus agalactiae 1023 ermB Streptococcus pneumoniae 1016susceptible Streptococcus pneumoniae 1046 ermB Streptococcus pneumoniae1095 ermB Streptococcus pneumoniae 1175 mefE Haemophilus influenzae 0085susceptible; acr AB-like Haemophilus influenzae 0131 susceptible; acrAB-like Moraxella catarrhalis 0040 susceptible Moraxella catarrhalis1055 erythromycin intermediate resistance Escherichia coli 0266susceptible; acr AB Haemophilus influenzae 1100 susceptible; acr AB-like

Assay II is utilized to test for activity against Pasteurella multocidaand Assay III is utilized to test for activity against Pasteurellahaemolytica.

ASSAY II

This assay is based on the liquid dilution method in microliter format.A single colony of P. multocida (strain 59A067) is inoculated into 5 mlof brain heart infusion (BHI) broth. The test compounds are prepared bysolubilizing 1 mg of the compound in 125 μl of dimethylsulfoxide (DMSO).Dilutions of the test compound are prepared using uninoculated BHIbroth. The concentrations of the test compound used range from 200 μg/mlto 0.098 μg/ml by two-fold serial dilutions. The P. multocida inoculatedBHI is diluted with uninoculated BHI broth to make a 10⁴ cell suspensionper 200 μl. The BHI cell suspensions are mixed with respective serialdilutions of the test compound, and incubated at 37° C. for 18 hours.The minimum inhibitory concentration (MIC) is equal to the concentrationof the compound exhibiting 100% inhibition of growth of P. multocida asdetermined by comparison with an uninoculated control.

Assay III

This assay is based on the agar dilution method using a SteersReplicator. Two to five colonies isolated from an agar plate areinoculated into BHI broth and incubated overnight at 37 ° C. withshaking (200 rpm). The next morning, 300 μl of the fully grown P.haemolytica preculture is inoculated into 3 ml of fresh BHI broth and isincubated at 37° C. with shaking (200 rpm). The appropriate amounts ofthe test compounds are dissolved in ethanol and a series of two-foldserial dilutions are prepared. Two ml of the respective serial dilutionis mixed with 18 ml of molten BHI agar and solidified. When theinoculated P. haemolytica culture reaches 0.5 McFarland standarddensity, about 5 μl of the P. haemolytica culture is inoculated onto BHIagar plates containing the various concentrations of the test compoundusing a Steers Replicator and incubated for 18 hours at 37° C. Initialconcentrations of the test compound range from 100-200 μg/ml. The MIC isequal to the concentration of the test compound exhibiting 100%inhibition of growth of P. haemolytica as determined by comparison withan uninoculated control.

The in vivo activity of the compounds of formula (I) can be determinedby conventional animal protection studies well known to those skilled inthe art, usually carried out in mice.

Mice are allotted to cages (10 per cage) upon their arrival, and allowedto acclimate for a minimum of 48 hours before being used. Animals areinoculated with 0.5 ml of a 3×10³ CFU/ml bacterial suspension (P.multocida strain 59A006) intraperitoneally. Each experiment has at least3 non-medicated control groups including one infected with 0.1Xchallenge dose and two infected with 1X challenge dose; a 10X challengedata group may also be used. Generally, all mice in a given study can bechallenged within 30-90 minutes, especially if a repeating syringe (suchas a Cornwall® syringe) is used to administer the challenge. Thirtyminutes after challenging has begun, the first compound treatment isgiven. It may be necessary for a second person to begin compound dosingif all of the animals have not been challenged at the end of 30 minutes.The routes of administration are subcutaneous or oral doses.Subcutaneous doses are administered into the loose skin in the back ofthe neck whereas oral doses are given by means of a feeding needle. Inboth cases, a volume of 0.2 ml is used per mouse. Compounds areadministered 30 minutes, 4 hours, and 24 hours after challenge. Acontrol compound of known efficacy administered by the same route isincluded in each test. Animals are observed daily, and the number ofsurvivors in each group is recorded. The P. multocida model monitoringcontinues for 96 hours (four days) post challenge.

The PD₅₀ is a calculated dose at which the compound tested protects 50%of a group of mice from mortality due to the bacterial infection whichwould be lethal in the absence of drug treatment.

The compounds of formula 1 and their pharmaceutically acceptable salts(hereinafter referred to, collectively, as “the active compounds of thisinvention” ) may be administered alone or in combination withpharmaceutically acceptable carriers, in either single or multipledoses. Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solutions and various organic solvents. Thepharmaceutical compositions formed by combining the active compounds ofthis invention can then be readily administered in a variety of dosageforms such as tablets, powders, lozenges, syrups, injectable solutionsand the like. These pharmaceutical compositions can, if desired, containadditional ingredients such as flavorings, binders, excipients and thelike. Thus, for purposes of oral administration, tablets containingvarious excipeints such as sodium citrate, calcium carbonate and calciumphosphate may be employed along with various disintegrants such asstarch, methylcellulose, alginic acid and certain complex silicates,together with binding agents such as polyvinylpyrrolidone, sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in soft and hard filled gelatin capsules. Preferred materialsfor this include lactose or milk sugar and high molecular weightpolyethylene glycols. When aqueous suspensions or elixirs are desiredfor oral administration, the essential active ingredient therein may becombined with various sweetening or flavoring agents, coloring matter ordyes and, if desired, emulsifying or suspending agents, together withdiluents such as water, ethanol, propylene glycol, glycerin andcombinations thereof.

For parenteral administration, solutions containing an active compoundof this invention or a pharmaceutically acceptable salt thereof insesame or peanut oil, aqueous propylene glycol, or in sterile aqueoussolution may be employed. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. These particular aqueous solutionsare especially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

To implement the methods of this invention, an effective dose of anactive compound of this invention is administered to a susceptible orinfected animal (including mammals, fish and birds) by parenteral (i.v.,i.m. or s.c.), oral, or rectal routes, or locally as a topicalapplication to the skin and/or mucous membranes. The route ofadministration will depend on the mammal, fish or bird that is beingtreated. The effective dose will vary with the severity of the disease,and the age, weight and condition of the animal. However, the daily dosewill usually range from about 0.25 to about 150 mg/kg body weight of thepatient to be treated, preferably from about 0.25 to about 25 mg/kg.

The Examples provided below illustrate specific embodiments of theinvention, but the invention is not limited in scope to the Examplesspecifically exemplified.

EXAMPLE 1

Compound of formula 1: R²=R³=R⁷=H, R¹=phenylbutyl

To a solution of9-deoxo-9-hydroxyimino-11-deoxy-5-O-desosaminyl-11-(3-phenylbutyl)hydrazo-6-O-methyl-3-oxoerythronolide A, 11,12-carbamate (formula 2,R₁=H, R₂=phenylbutyl) (50 mg, 0.06 mmol) in CHCl₃ (1 mL) was added 37%aqueous CH₂O (25 μL) followed by HCO₂H (23 μL). The resulting solutionwas heated at 65° C. for 2 hours. The reaction was diluted withsaturated NaHCO₃, and CH₂Cl₂ was added. The organic layer was separated,and the aqueous layer was extracted with CH₂Cl₂. The combined organiclayers were washed with brine, dried over MgSO₄, and concentrated invacuo. The residue was purified by preparative TLC (89% CH₂Cl₂-9%MeOH-1% NH₃.H₂O) to afford the title compound as a white solid.

¹H NMR (400 MHz, CDCl₃)δ: 7.28-7.08 (5H, m), 5.36 (1H, d, J=14.4 Hz),4.91 (1H, dd, J=10.8 and 2.4 Hz), 4.79 (1H, d, J=14.4 Hz), 4.34 (1H, d,J=8.0Hz), 4.28 (1H, d, J=7.2Hz), 3.96 (1H, s), 3.83 (1H, q, J=6.8 Hz),3.19 (1H, dd, J=7.6 and 10.0 Hz), 3.03 (1H, dq, J=7.6 and 8.0 Hz), 2.79(3H, s), 2.62 (1H, q, J=6.8 Hz), 2.60 (2H, t, J=7.2 Hz), 2.47 (1H, dt,J=11.2 and 3.6 Hz), 2.27 (6H, s), 1.52 (3H, s), 1.46 (3H, s), 1.35 (3H,d, J=6.8 Hz), 1.30 (3H, d, J=7.6 Hz), 1.29 (3H, d, J=7.6 Hz), 1.23 (3H,d, J=6.4 Hz), 0.99 (3H, d, J=7.2 Hz), 0.82 (3H, t, J=7.6 Hz),

Exact mass calcd. for C₄₂H₆₇N₄O₁₀ (M+H): 787.4867; found: 787.4863.

EXAMPLE 2

Compound of formula 1: R²=R³=R⁷=H, R¹=3-quinolin-4-yl-propyl

To a solution of9-deoxo-9-hydroxyimino-11-deoxy-5-O-desosaminyl-11-(3-quinolin-4-yl-propyl)hydrazo-6-O-methyl-3-oxoerythronolideA, 11,12-carbamate (formula 2, R₁=H, R₂=3-quinolin-4-yl-propyl) (187 mg,0.23 mmol) in CHCl₃ (11 mL) was added 37% aqueous CH₂O (88 μL) followedby HCO₂H (81 μL). The resulting solution was heated at 65° C. for 2hour. The reaction was diluted with saturated NaHCO₃, and CH₂Cl₂ wasadded. The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over MgSO₄, and concentrated invacuo. The residue waspurified by preparative TLC (89% CH₂Cl₂-9% MeOH-1% NH₃.H₂O) to affordthe title compound as a white solid (121 mg).

¹H NMR (400 MHz, CDCl₃)δ: 8.76 (1H, d, J=4.4 Hz), 8.10 (1H, d, J=8.4Hz), 8.07 (1H, d, J=8.8 Hz), 7.66 (br. t, J=7.2 Hz), 7.50 (1H, br. t,J=7.2 Hz), 7.27 (1H, d, J=4.8 Hz), 5.54 (1H, d, J=14.4Hz), 4.78 (1H, d,J=14.8 Hz), 3.84 (1H, q, J=6.8Hz), 2.80 (3H, s), 2.30 (6H, s), 2.53 (3H,s), 1.47 (3H, s), 1.35 (3H, d, J=7.2 Hz), 1.33 (3H, d, J=7.6 Hz), 1.29(3H, d, J=7.2 Hz), 1.23 (3H, d, J=6.0 Hz), 0.99 (3H, d, J=7.2 Hz), and0.77 (3H, t, J=7.6 Hz).

¹³C NMR (100 MHz, CDCl₃)δ: 203.58, 169.98, 157.63, 154.66, 150.11,148.25, 147.95, 130.02, 129.01, 127.53, 126.34, 123.73, 121.05, 85.08,81.07, 78.87, 77.78, 76.61, 70.27, 69.53, 65.89, 56.67, 51.49, 50.93,50.65, 47.56, 40.23 (2C), 38.30, 31.07, 28.86, 28.35, 28.23, 28.17,21.76, 21.17, 20.69, 18.82, 15.42, 14.72,13.47,12.55, and 10.37.

Exact mass calcd. for C₄₂H₆₇N₄O₁₀(M+H): 824.4810; found: 824.4796.

EXAMPLE 3

Compound of formula 1: R²=R³=R⁷=H, R¹=3-(4-phenyl-imidazol-1-yl)-propyl

To a solution of9-deoxo-9-hydroxyimino-11-deoxy-5-O-desosaminyl-11-(3-(4-phenyl-imidazol-1-yl)-propyl)hydrazo-6-O-methyl-3-oxoerythronolideA, 11,12-carbamate (formula 2, R₁=H,R₂=3-(4-phenyl-imidazol-1-yl)-propyl) (15 mg, 0.02 mmol) in CHCl₃ (1 mL)was added 37% aqueous CH₂O (7 μL) followed by HCO₂H (7 μL). Theresulting solution was heated at 65°0 C. for 2 hours. The reaction wasdiluted with saturated NaHCO₃, and CH₂Cl₂ was added. The organic layerwas separated, and the aqueous layer was extracted with CH₂Cl₂. Thecombined organic layers were washed with brine, dried over MgSO₄, andconcentrated in vacuo. The residue was purified by preparative TLC (89%CH₂Cl₂-9% MeOH-1% NH₃.H₂O) to afford the title compound as a white solid(13 mg).

¹H NMR (400 MHz, CDCl₃)δ: 7.75-7.15 (7H), 5.51 (1H, d, J=14.8 Hz), 4.86(1H, dd, J=1.6 and 10.4 Hz), 4.71 (1H, d, J=14.8 Hz), 4.32 (1H, d, J=8.4Hz), 4.27 (1H, d, J=7.2 Hz), 3.93 (1H, s), 3.83 (1H, q, J=6.8 Hz), 2.76(3H, s), 2.31 (6H, s), 1.53 (3H, s), 1.45 (3H, s), 1.34 (3H, d, J=6.8Hz), 1.32 (3H, J=6.8 Hz), 1.28 (3H, d, J=7.6 Hz), 1.23 (3H, d, J=6.0Hz), 0.98 (3H, d, J=7.2 Hz) and 0.80 (3H, t, J=7.2 Hz).

Exact mass calcd. for C₄₄H₆₇N₆O₁₀ (M+H): 839.4914; found: 839.4904.

EXAMPLE 4

Compound of formula 1: R²=R³=R⁷=H, R¹=3-(2-methoxyphenyl)-propyl

To a solution of9-deoxo-9-hydroxyimino-11-deoxy-5-O-desosaminyl-11-(3-(2-methoxyphenyl)-propyl)hydrazo-6-O-methyl-3-oxoerythronolideA, 11,12-carbamate (formula 2, R₁=H, R₂=3-(2-methoxyphenyl)-propyl (15mg, 0.02 mmol) in CHCl₃ (1 mL) was added 37% aqueous CH₂O (7 μL)followed by HCO₂H (7 μL). The resulting solution was heated at 65° C.for 2 hours. The reaction was diluted with saturated NaHCO₃, and CH₂Cl₂was added. The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over MgSO₄, and concentrated in vacuo. The residue waspurified by preparative TLC (89% CH₂Cl₂-9% MeOH-1% NH₃.H₂O) to affordthe title compound as a white solid (163 mg).

¹H NMR (400 MHz, CDCl₃)δ: 7.13 (2H), 6.79 (2H), 5.48 (1H, d, J=14.8 Hz),4.95 (1H, dd, J=2.4 and 10.8 Hz), 4.79 (1H, d, J=14.8 Hz), 4.32 (1H, d,J=7.6 Hz), 4.29 (1H, d, J=7.2 Hz), 3.98 (1H, s), 3.76 (3H, s), 2.78 (3H,s), 2.33 (6H, s), 1.52 (3H, s), 1.45 (3H, s), 1.35 (3H, d, J =6.8 Hz),1.31 (3H, d, J=6.8 Hz), 1.29 (3H, d, J=7.6 Hz), 1.24 (3H, d, J=6.4 Hz),0.99 (3H, d, J=6.8 Hz) and 0.83 (3H, t, J=7.6 Hz).

MS: m/z 803 (M+H).

EXAMPLE 5

Compound of formula 1: R²=R³=R⁷=H, R¹=3-furan-2-yl-propyl

To a solution of9-deoxo-9-hydroxyimino-11-deoxy-5-O-desosaminyl-11-(3-furan-2-yl-propyl)hydrazo-6-O-methyl-3-oxoerythronolideA, 11,12-carbamate (formula 2, R₁=H, R₂=3-furan-2-yl-propyl (15 mg, 0.02mmol) in CHCl₃ (1 mL) was added 37% aqueous CH₂O (7 μL) followed byHCO₂H (7 μL). The resulting solution was heated at 65° C. for 2 hours.The reaction was diluted with saturated NaHCO₃, and CH₂Cl₂ was added.The organic layer was separated, and the aqueous layer was extractedwith CH₂Cl₂. The combined organic layers were washed with brine, driedover MgSO₄, and concentrated in vacuo. The residue was purified bypreparative TLC (89% CH₂Cl₂-9% MeOH-1% NH₃.H₂O) to afford the titlecompound as a white solid.

¹H NMR (400 MHz, CDCl₃)δ: 7.25 (1H), 6.21 (1H), 5.98 (1H), 5.47 (1H, d,J=14.4 Hz), 4.93 (1H, dd, J=2.0 and 10.4 Hz), 4.77 (1H, d, J=14.4 Hz),4.32 (1H, d, J=7.6 Hz), 4.27 (1H, d, J=7.2 Hz), 3.96 (1H, s), 3.83 (1H,q, J=6.8 Hz), 3.17 (1H, dd, J=7.2 and 10.0 Hz), 2.77 (3H, s), 2.25 (6H,s), 1.52 (3H, s), 1.46 (3H, s), 1.35 (2H, d, J=6.8 Hz), 1.31 (3H, d,J=6.8 Hz), 1.29 (3H, d, J=6.8 Hz), 1.23 (3H, d, J=6.0 Hz), 0.98 (3H, d,J=6.8 Hz), and 0.85 (3H, t, J=7.2 Hz).

MS: m/z 763 (M+H).

EXAMPLE 6

Compound of formula 1: R²=R³=R⁷=H, R²=3-benzoimidazol-1-yl-propyl

To a solution of9-deoxo-9-hydroxyimino-11-deoxy-5-O-desosaminyl-11-(3-benzoimidazol-1-yl-propyl)hydrazo-6-O-methyl-3-oxoerythronolideA, 11,12-carbamate (formula 2, R₁=H, R₂=3-benzoimidazol-1-yl-propyl (15mg, 0.02 mmol) in CHCl₃ (1 mL) was added 37% aqueous CH₂O (7 μL)followed by HCO₂H (7 μL). The resulting solution was heated at 65° C.for 2 hours. The reaction was diluted with saturated NaHCO₃, and CH₂Cl₂was added. The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over MgSO₄, and concentrated in vacuo. The residue waspurified by preparative TLC (89% CH₂Cl₂-9% MeOH-1% NH₃.H₂O) to affordthe title compound as a white solid.

¹H NMR (400 MHz, CDCl₃)δ: 7.94 (1H, s), 7.77 (1H), 7.46 (1H), 7.24 (2H),5.52 (1H, d, J =14.4 Hz), 4.90 (1H, dd, J=1.6 and 10.8 Hz), 4.63 (1H, d,J=14.4 Hz), 4.31 (1H, d, J=8.0 Hz), 4.29 (1H, d, J=7.2 Hz), 3.94 (1H,s), 3.83 (1H, q, J=6.8 Hz), 2.74 (3H, s), 2.41 (6H, s), 1.54 (3H, s),1.43 (3H, s), 1.33 (6H, d, J=6.8 Hz), 1.28 (3H, d, J=7.6 Hz), 1.24 (3H,d, J=6.0 Hz), 0.98 (3H, d, J=7.2 Hz), and 0.82 (3H, t, J=7.2 Hz).

MS: m/z 813 (M+H).

EXAMPLE 7

Compound of formula 1: R²=R³=R⁷=H, R¹=3-indazol-1-yl-propyl

To a solution of9-deoxo-9-hydroxyimino-11-deoxy-5-O-desosaminyl-11-(3-indazol-1-yl-propyl)hydrazo-6-O-methyl-3-oxoerythronolideA, 11,12-carbamate (formula 2, R₁=H, R₂=3-indazol-1-yl-propyl) (19 mg,0.02 mmol) in CHCl₃ (1 mL) was added 37% aqueous CH₂O (9 μL) followed byHCO₂H (8 μL). The resulting solution was heated at 65° C. for 2 hours.The reaction was diluted with saturated NaHCO₃, and CH₂Cl₂ was added.The organic layer was separated, and the aqueous layer was extractedwith CH₂Cl₂. The combined organic layers were washed with brine, driedover MgSO₄, and concentrated in vacuo. The residue was purified bypreparative TLC (89% CH₂Cl₂-9% MeOH-1% NH₃.H₂O) to afford the titlecompound as a white solid.

¹H NMR (400 MHz, CDCl₃)δ:7.97 (1H, s), 7.66 (1H, d, J=7.6 Hz), 7.65 (1H,d, J=8.0 Hz), 7.31 (1H, br. t, J=6.0 Hz), 7.07 (1H, br. t, J=6.0 Hz),5.44 (1H, d, J=14.4 Hz), 4.92 (1H, dd, J=2.4 and 10.4 Hz), 4.43 (1H, d,J=14.4 Hz), 4.30 (1H, t, J=8.0 Hz), 3.95 (1H, s), 3.81 (1H, q, J=6.8Hz), 2.71 (3H, s), 2.43 (6H, s), 1.54 (3H, s), 1.39 (3H, s), 1.34 (3H,d, J=6.8 Hz), 1.33 (3H, d, J=m6.8 Hz), 1.27 (3H, d, J=7.6 Hz), 1.24 (3H,d, J=6.0 Hz), 0.97 (3H, d, J=6.8 Hz) and 0.82 (3H, t, J=7.6 Hz). MS: m/z813 (M+H).

EXAMPLE 8

Compound of formula 1: R²=R³=R⁷=H, R¹=3-(4-hydroxy-phenyl)-propyl

To a solution of9-deoxo-9-hydroxyimino-11-deoxy-5-O-desosaminyl-11-(3-(4-hydroxy-phenyl)-propyl)hydrazo-6-O-methyl-3-oxoerythronolideA, 11,12-carbamate (formula 2, R₁=H,R₂=3-(4-hydroxy-phenyl)-indol-propyl) (24 mg, 0.03 mmol) in CHCl₃ (1 mL)was added 37% aqueous CH₂O (12 μL) followed by HCO₂H (11 μL). Theresulting solution was heated at 65° C. for 2 hours. The reaction wasdiluted with saturated NaHCO₃, and CH₂Cl₂ was added. The organic layerwas separated, and the aqueous layer was extracted with CH₂Cl₂. Thecombined organic layers were washed with brine, dried over MgSO₄, andconcentrated in vacuo. The residue was purified by preparative TLC (89%CH₂Cl₂-9% MeOH-1% NH₃.H₂O) to afford the title compound as a whitesolid.

¹H NMR (400 MHz, CDCl₃)δ: 6.96 (2H, d, J=8.4 Hz), 6.68 (2H, d, J=8.4Hz), 5.47 (1H, d, J=14.8 Hz), 4.95 (1H, dd, J=2.4 and 10.8 Hz), 4.78(1H, d, J=14.8 Hz), 4.34 (1H, d, J=7.6 Hz), 4.27 (1H, d, J=7.2 Hz), 3.98(1H, s), 3.84 (1H, q, J=7.2 Hz), 3.18 (1H, dd, J=7.2 and 10.4 Hz), 2.80(3H, s), 2.26 (6H, s), 1.52 (3H, s), 1.46 (3H, s), 1.35 (3H, d, J=6.4Hz), 1.31 (3H, d, J=6.4 Hz), 1.30 (3H, d, J=6.4 Hz), 1.23 (3H, d, J=6.0Hz), 0.99 (3H, d, J=7.2 Hz), and 0.83 (3H, t, J=7.2 Hz).

MS: m/z 789 (M+H).

EXAMPLE 9

Compound of formula 1: R²=R³=R⁷=H, R¹=3-(1H-indol-3-yl)-propyl

To a solution of9-deoxo-9-hydroxyimino-11-deoxy-5-O-desosaminyl-1-(3-(1H-indol-3-yl)-propyl)hydrazo-6-O-methyl-3-oxoerythronolideA, 11,12-carbamate (formula 2, R₁=H, R₂=3-(1H-indol-3-yl)-propyl) (15mg, 0.02 mmol) in CHCl₃ (1 mL) was added 37% aqueous CH₂O (8 μL)followed by HCO₂H (7 μL). The resulting solution was heated at 65° C.for 2 hours. The reaction was diluted with saturated NaHCO₃, and CH₂Cl₂was added. The organic layer was separated, and the aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over MgSO₄, and concentrated in vacuo. The residue waspurified by preparative TLC (89% CH₂Cl₂-9% MeOH-1% NH3.H₂O) to affordthe title compound as a white solid.

¹H NMR (400 MHz, CDCl₃)δ: 7.54 (1H, d, J=7.6 Hz), 7.44 (1H, d, J=8.0Hz), 7.17 (1H, t, J=7.2 Hz), 7.09 (1H, t, J=6.8 Hz), 6.99 (1H, s), 5.57(1H, br.s), 5.43 (1H, d, J=14.8 Hz), 4.86 (1H, dd, J=2.4 and 10.8 Hz),4.76 (1H, d, J=14.8 Hz), 4.23 (1H, d, J=7.2 Hz), 4.22 (1H, d, J=8.4Hz),3.89 (1H, s), 3.79 (1H, q, J=6.8Hz), 3.16 (1H, dd, J=7.2 and 10.4Hz),2.44 (3H, s), 2.25 (6H, s), 1.50 (3H, s), 1.36 (3H, d, J=7.2 Hz), 1.29(3H, d, J=6.8 Hz), 1.26 (3H, d, J=8.0 Hz), 1.21 (3H, d, J=6.0 Hz), 0.96(3H, d, J=7.2 Hz) and 0.81 (3H, t, J=7.2 Hz).

MS: m/z 812 (M+H).

EXAMPLE 10

Compound of formula 1: R²=R³=R⁷=H,R¹=3-(4-pyridin-3-yl-imidazol-1-yl)-propyl

To a solution of9-deoxo-9-hydroxyimino-11-deoxy-5-O-desosaminyl-11-(3-(4-pyridin-3-yl-imidazol-1-yl)-propyl)hydrazo-6-O-methyl-3-oxoerythronolideA, 11,12-carbamate (formula 2, R⁷=H,R¹=3-(4-pyridin-3-yl-imidazol-1-yl)propyl) (231 mg, 0.28 mmol) in CHCl₃(4 mL) was added 37% aqueous CH₂O (110 μL) followed by HCO₂H (100 μL).The resulting solution was heated at 65° C. for 2 hours. The reactionwas diluted with saturated NaHCO₃, and CH₂Cl₂ was added. The organiclayer was separated, and the aqueous layer was extracted with CH₂Cl₂.The combined organic layers were washed with brine, dried over MgSO₄,and concentrated in vacuo. The residue was purified by preparative TLC(89% CH₂Cl₂-9% MEOH-1% NH₃.H₂O) to afford the title compound as a whitesolid.

¹H NMR (400 MHz, CDCl₃)δ:8.93 (1H, d, J=2.0 Hz), 8.43 (1H, dd, J=1.2,.4Hz), 8.04 (1H, dt, J=1.6, 7.6 Hz), 7.56 (1H, s), 7.31 (1H, s), 7.24 (1H,dd, J=4.0, 6.4 Hz), 5.52 (1H, d, J=14.4 Hz), 4.85 (1H, d, J=10.8 Hz),4.71 (1H, d, J=14.8 Hz), 4.32 (1H, d, J=7.6 Hz), 4.21 (1H, t, J=6.8 Hz),4.01 (1H, m), 3.93 (1H, s), 383 (1H, q, J=6.8 Hz), 2.75 (3H, s), 2.58(6H, s), 1.33 (6H, d, J=7.2 Hz), 1.27 (3H, d, J=6.0 Hz), 1.25 (3H, d,J=6.2 Hz), 1.00 (3H, d, J=7.2 Hz), and 0.81 (3H, d, J=7.2 Hz).

MS: m/z 840 (M+H).

What is claimed is:
 1. A compound of the formula

on pharmaceutically acceptable salts thereof, wherein: R¹ is selectedfrom H the group consisting of —(CR⁴R⁵)_(m)R⁶, —C(O)(CR⁴R⁵)_(m)R⁶,—C(O)O(CR⁴R⁶)_(m)R⁶, and —C(O)NR⁴(CR4R⁵)_(m)R⁶, wherein m is an integerranging from 0 to 6 and both R⁴ and R⁵ may vary for each iteration wherem is greater than 1; each R² and R³ are independently selected from thegroup consisting of H and C₁-C₁₈ alkyl, wherein one or two carbons ofsaid alkyl are optionally replaced by a heteroatom selected from thegroup consisting of O, S and N, and are optionally substituted by 1 to 3substituents independently selected from the group consisting of—C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl, C₁-C₁₀ alkanoyl, halo, nitro,cyano, C₁-C₁₀ alkyl, 4-10 membered heterocyclic, C₆-C₁₀ aryl,—NH(C₁-C₁₀)alkyl, —S(C₁-C₁₀ alkyl), —SO(C₁-C₁₀)alkyl, —SO₂(C₁-C₁₀)alkyland —SO₂N(C₁-C₁₀)alkyl, provided that two O atoms, two S atoms or an Sand an O atom are not bonded to each other; each R⁴ and R⁵ areindependently selected from the group consisting of H, halo and C₁-C₆alkyl, wherein 1 to 3 carbons of said alkyl are optionally replaced by aheteroatom selected from the group consisting of O, S and N and each R⁴and R⁵ may vary independently when m is greater than 1, provided thattwo O atoms, two S atoms or an S and an O atom are not bonded to eachother; or each R⁴ and R⁵ taken together with the carbon to which theyare attached can form a 3-10 membered ring, wherein one or more carbonsof said ring are optionally replaced by a heteroatom selected from thegroup consisting of O, S and N, and are optionally substituted by 1 to 3substituents independently selected from the group consisting of—C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl, C₁-C₁₀ alkanoyl, halo, nitro,cyano, C₁-C₁₀ alkyl, 4-10 membered heterocyclic, C₆-C₁₀ aryl,—NH(C₁-C₁₀)alkyl, —N((C₁-C₁₀)alkyl)₂, —S(C₁-C₁₀)alkyl, —SO(C₁-C₁₀)alkyl,—SO₂(C₂(C₁-C₁₀)alkyl and —SO₂N(C₁-C₁₀)alkyl, provided that two O atoms,two S atoms or an S and an O atom are not bonded to each other; R⁶ is(C₁-C₁₈)alkyl, a 4-10 membered heterocyclic or C₆-C₁₀ aryl, wherein 1 to3 carbons of said alkyl are optionally replaced by a heteroatom selectedfrom the group consisting of O, S and N and said heterocycic and arylgroups are optionally substituted by 1 to 3 substituents independentlyselected from the group consisting of —C(O)O(C₁-C₁₀)alkyl,—O(C₁-C₁₀)alkyl, C₁-C₁₀ alkanoyl, halo, nitro, cyano, (C₁-C₁₀) alkyl,—NH(C₁-C₁₀)alkyl, —N((C₁-C₁₀)alkyl)₂, —S(C₁-C₁₀ alkyl),—SO(C₁-C₁₀)alkyl, —SO₂(C₁-C₁₀)alkyl and —SO₂N(C₁-C₁₀)alkyl, providedthat two O atoms, two S atoms or an S and an O atom are not bonded toeach other; and R⁷ is H, —C(O)O(C₁-C₁₈)alkyl or —C(O)(C₁-C₁₈)alkyl,wherein 1 to 3 carbons of said alkyl are optionally replaced by aheteroatom selected from the group consisting of O, S and N and whereinin the alkyl portion of said alkanoyl one or two carbons optionally maybe replaced by a heteroatom selected from O, S and N, provided that twoO atoms, two S atoms or an S and an O atom are not bonded to each other.2. The compound of claim 1 wherein R₇ is H.
 3. The compound of claim 1wherein R³ is H.
 4. The compound of claim 1 wherein R³=R²=H.
 5. Thecompound of claim 1 wherein R³=R²=R⁷=H.
 6. The compound of claim 1wherein wherein R¹ is (CH₂)_(m)R⁶, wherein m is an integer ranging from0 to
 6. 7. The compound of claim 6 wherein R⁶ is selected from the groupconsisting of: quinolin4-yl, quinolin-5-yl, quinolin-8-yl,4-phenyl-1-imidazol-1-yl, 4-pyridin-3-yl-imidazol-1-yl andimidazo(4,5-b)pyridin-3-yl.
 8. The compound of claim 6 wherein m is 3.9. The compound of claim 8 wherein R⁶ is selected from the groupconsisting of: quinolin4-yl, quinolin-5-yl, quinolin-8-yl,4-phenyl-1-imidazol-1-yl, 4-pyridin-3-yl-imidazol-1-yl andimidazo(4,5-b)pyridin-3-yl.
 10. The compound of claim 1 selected fromthe group consisting of: the compound of formula 1 wherein R⁷=H,R³=R²=H, R¹=3-quinolin4-yl-propyl; the compound of formula 1 whereinR⁷=H, R³=R²=H, R¹=7-methoxy-quinolin4-yl)-propyl; the compound offormula 1 wherein R⁷=H, R³=R²=H, R¹=3-benzoimidazol-1-yl-propyl; thecompound of formula 1 wherein R⁷=H, R³=R²=H, R¹=3-indol-1-yl-propyl; thecompound of formula 1 wherein R⁷=H, R³=R²=H, R¹=3-indazol-1-yl-propyl;the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-carbazol-1-yl-propyl; the compound of formula 1 wherein R⁷=H,R³=R²=H, R¹=3-(5-phenyl-1H-pyrrol-2-yl)-propyl; the compound of formula1 wherein R⁷=H, R³=R²=H, R¹=3-(4-phenyl-imidazol-1-yl)-propyl; thecompound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(imidazo(4,5-b)pyridin-3-yl)-propyl; the compound of formula 1wherein R⁷=H, R³=R²=H, R¹=3-(4-pyridin-3-yl-imidazol-1-yl)-propyl; thecompound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(3-(4-chlorophenyl)-(1,2,4)oxadizol-5-yl)-propyl; the compound offormula 1 wherein R⁷=H, R³=R²=H,R¹=3-(3-(4-methoxyphenyl)-(1,2,4)oxadizol-5-yl)-propyl; the compound offormula 1 wherein R⁷=H, R³=R²=H,R¹=3-(3-(4-pyridin-4-yl)-(1,2,4)oxadizol-5-yl)-propyl; the compound offormula 1 wherein R⁷=H, R³=R²=H, R¹=3-benzotriazol-1-yl-propyl; thecompound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-benzotriazol-2-yl-propyl; the compound of formula 1 wherein R⁷=H,R³=R²=H, R¹=3-(1H-indol-3-yl)-propyl; the compound of formula 1 whereinR⁷=H, R³=R²=H, R¹=3-pyridin4-yl-propyl; the compound of formula 1wherein R⁷=H, R³=R²=H, R¹=3-pyridin-3-yl-propyl; the compound of formula1 wherein R⁷=H, R³=R²=H, R¹=3-pyridin-2-yl-propyl; the compound offormula 1 wherein R⁷=H, R³=R²=H, R¹=3-phenylpropyl; the compound offormula 1 wherein R⁷=H, R³=R²=H, R¹=3-(2-methoxyphenyl)-propyl; thecompound of formula 1 wherein R⁷=H, R³=R²=H, R¹=3-furan-2-yl-propyl; thecompound of formula 1 wherein R⁷=H, R³=R²=H, R¹=3-thiophen-2-yl-propyl;the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-thiophen-2-yl-propyl; the compound of formula 1 wherein R⁷=H,R³=R²=H, R¹=3-pyrrol-1-yl- propyl; the compound of formula 1 whereinR⁷=H, R³=R²=H, R¹=3-(2-pyridin-3-yl-thiazol-4-yl )-propyl; the compoundof formula 1 wherein R⁷=H, R³=R²=H, R¹=3-(2-phenyl-thiazol-5-yl)-propyl;the compound of formula 1 wherein R⁷=H, R³=R²=H,R¹=3-(2-phenyl-thiazol-5-yl)-propyl; the compound of formula 1 whereinR⁷=H, R³=R²=H, R¹=3-(4-phenyl-1H-imidazol-2-yl)-propyl; andpharmaceutically acceptable salts of the foregoing compounds.
 11. Apharmaceutical composition for the treatment of a bacterial infection orprotozoa infection in a mammal, fish, or bird which comprises atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 12. A method of treating a bacterial infection or aprotozoa infection in a mammal, fish, or bird which comprisesadministering to said mammal, fish, or bird a therapeutically effectiveamount of a compound of claim
 1. 13. A method of preparing a compound ofthe formula

or pharmaceutically acceptable salts thereof, wherein: R¹is selectedfrom the group consisting of H, —(CR⁴R⁵)_(m)R⁶, —C(O)(CR⁴R⁵)_(m)R⁶,—C(O)O(CR⁴R⁵)_(m)R⁶, and —C(O)NR⁴(CR⁴R⁵)_(m)R⁶, wherein m is an integerranging from 0 to 6 and both R⁴ and R⁵ may vary for each iteration wherem is greater than 1; each R² and R³ are independently selected from thegroup consisting of H and C₁-C₁₈ alkyl, wherein one or two carbons ofsaid alkyl are optionally replaced by a heteroatom selected from thegroup consisting of O, S and N, and are optionally substituted by 1 to 3substituents independently selected from the group consisting of—C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl, C₁-C₁₀ alkanoyl, halo, nitro,cyano, C₁-C₁₀ alkyl, 4-10 membered heterocyclic, C₆-C₁₀ aryl,—NH(C₁-C₁₀)alkyl, —S(C₁-C₁₀ alkyl), —SO(C₁-C₁₀)alkyl, —SO₂(C_(1-C)₁₀)alkyl and —SO₂N(C_(1-C) ₁₀)alkyl, provided that two O atoms, two Satoms or an S and an O atom are not bonded to each other; each R⁴ and R⁵are independently selected from the group consisting of H, halo andC_(1-C) ₆ alkyl, wherein 1 to 3 carbons of said alkyl are optionallyreplaced by a heteroatom selected from the group consisting of O, S andN and each R⁴ and R⁵ may vary independently when m is greater than 1,provided that two O atoms, two S atoms or an S and an O atom are notbonded to each other; or each R⁴ and R⁵ taken together with the carbonto which they are attached can form a 3-10 membered ring, wherein one ormore carbons of said ring are optionally replaced by a heteroatomselected from the group consisting of O, S and N, and are optionallysubstituted by 1 to 3 substituents independently selected from the groupconsisting of —C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl, C₁-C₁₀ alkanoyl,halo, nitro, cyano, C₁-C₁₀ alkyl, 4-10 membered heterocyclic, C₆-C₁₀aryl, —NH(C₁-C₁₀)alkyl, —N((C₁-C₁₀)alkyl)₂, —S(C₁-C₁₀)alkyl, —SO(C₁-C₁₀)alkyl, —SO₂(C₂(C₁-C₁₀)alkyl and —SO₂N(C₁-C₁₀)alkyl, provided that two Oatoms, two S atoms or an S and an O atom are not bonded to each other;R⁶ is (C₁-C₁₈)alkyl, a 4-10 membered heterocyclic or C₆-C₁₀ aryl,wherein 1 to 3 carbons of said alkyl are optionally replaced by aheteroatom selected from the group consisting of O, S and N and saidheterocycic and aryl groups are optionally substituted by 1 to 3substituents independently selected from the group consisting of—C(O)O(C₁-C₁₀)alkyl, —O(C₁-C₁₀)alkyl, C₁-C₁₀ alkanoyl, halo, nitro,cyano, (C₁-C₁₀) alkyl, —NH(C₁-C₁₀)alkyl, —N((C₁-C₁₀)alkyl)₂, —S(C₁-C₁₀alkyl), —SO(C₁-C₁₀)alkyl, —SO₂(C₁-C₁₀)alkyl and —SO₂N(C₁-C₁₀)alkyl,provided that two O atoms, two S atoms or an S and an O atom are notbonded to each other; and R⁷ is H, —C(O)O(C₁-C₁₈)alkyl or—C(O)(C₁-C₁₈)alkyl, wherein 1 to 3 carbons of said alkyl are optionallyreplaced by a heteroatom selected from the group consisting of O, S andN and wherein in the alkyl portion of said alkanoyl one or two carbonsoptionally may be replaced by a heteroatom selected from the groupconsisting of O, S and N, provided that two O atoms, two S atoms or an Sand an O atom are not bonded to each other, which comprises treating acompound of the formula

wherein R⁷ and R¹ are as defined above, with a compound of the formulaR³R²C=O, wherein R³ and R² are as defined for the compound of formula 1,in the presence of an acid.
 14. The method of claim 13 wherein thecompound of the formula R³R²C=O is CH₂O.
 15. The method of claim 13wherein the acid is selected from the group consisting of: acetic acid,formic acid, para-toluene sulfonic acid and proprionic acid.
 16. Acompound of the formula

or pharmaceutically acceptable salts thereof, wherein: R¹ is selectedfrom the group consisting of H, —(CR⁴R⁵)_(m)R⁶, —C(O)(CR⁴R⁵)_(m)R⁶,—C(O)O(CR⁴R⁵)_(m)R⁶, and —C(O)NR⁴(CR⁴R⁵)_(m)R⁶, wherein m is an integerranging from 0 to 6 and both R⁴ and R⁵ may vary for each iteration wherem is greater than 1; each R⁴ and R⁵ are independently selected from thegroup consisting of H, halo and C₁-C₆ alkyl, wherein 1 to 3 carbons ofsaid alkyl are optionally replaced by a heteroatom selected from thegroup consisting of O, S and N and each R⁴ and R⁵ may vary independentlywhen m is greater than 1, provided that two O atoms, two S atoms or an Sand an O atom are not bonded to each other; or each R⁴ and R⁵ takentogether with the carbon to which they are attached can form a 3-10membered ring, wherein one or more carbons of said ring are optionallyreplaced by a heteroatom selected from the group consisting of O, S andN, and are optionally substituted by 1 to 3 substituents independentlyselected from the group consisting of —C(O)O(C₁-C₁₀)alkyl,—O(C₁-C₁₀)alkyl, C₁-C₁₀ alkanoyl, halo, nitro, cyano, C₁-C₁₀ alkyl, 4-10membered heterocyclic, C₆ _(C) ₁₀ aryl, —NH(C₁-C₁₀)alkyl,—N((C₁-C₁₀)alkyl)₂, —S(C₁-C₁₀)alkyl, —SO(C₁-C₁₀)alkyl,—SO₂(C₂(C₁-C₁₀)alkyl and —SO₂N(C₁-C₁₀)alkyl, provided that two O atoms,two S atoms or an S and an O atom are not bonded to each other; and R⁶is (C₁-C₁₈)alkyl, a 4-10 membered heterocyclic or C₆-C₁₀ aryl, wherein 1to 3 carbons of said alkyl are optionally replaced by a heteroatomselected from the group consisting of O and N and said heterocycic andaryl groups are optionally substituted by 1 to 3 substituentsindependently selected from the group consisting of —C(O)O(C₁-C₁₀)alkyl,—O(C₁-C₁₀)alkyl, C₁-C₁₀ alkanoyl, halo, nitro, cyano, (C₁-C₁₀) alkyl,—NH(C₁-C₁₀)alkyl, —N((C₁-C₁₀)alkyl)₂, —S(C₁-C₁₀ alkyl),—SO(C₁-C₁₀)alkyl, —SO₂(C₁-C₁₀)alkyl and —SO₂N(C₁-C₁₀)alkyl, providedthat two O atoms, two S atoms or an S and an O atom are not bonded toeach other.
 17. A compound of the formula

or pharmaceutically acceptable salts thereof, wherein: R¹ is selectedfrom the group consisting of: phenylbutyl, 3-quinolin4-yl-propyl,3-(4-phenyl-imadazol-1-yl)-propyl, 3-(2-methoxyphenyl)-propyl,3-furan-2-yl-propyl, 3-benzoimidazol-1-yl-propyl, 3-indazol-1-yl-propyl,3-(4-hydroxy-phenyl)-propyl, 3-(1H-indol-3-yl)-propyl, and3-(4-pyridin-3-yl-imidazol-1 -yl)-propyl.